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GluN2B in corticostriatal circuits governs choice learning and choice shifting

Nature Neuroscience volume 16, pages 1101–1110 (2013)Cite this article

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Abstract

A choice that reliably produces a preferred outcome can be automated to liberate cognitive resources for other tasks. Should an outcome become less desirable, behavior must adapt in parallel or it becomes perseverative. Corticostriatal systems are known to mediate choice learning and flexibility, but the molecular mechanisms of these processes are not well understood. We integrated mouse behavioral, immunocytochemical, in vivo electrophysiological, genetic and pharmacological approaches to study choice. We found that the dorsal striatum (DS) was increasingly activated with choice learning, whereas reversal of learned choice engaged prefrontal regions. In vivo, DS neurons showed activity associated with reward anticipation and receipt that emerged with learning and relearning. Corticostriatal or striatal deletion of Grin2b (encoding the NMDA-type glutamate receptor subunit GluN2B) or DS-restricted GluN2B antagonism impaired choice learning, whereas cortical Grin2b deletion or OFC GluN2B antagonism impaired shifting. Our convergent data demonstrate how corticostriatal GluN2B circuits govern the ability to learn and shift choice behavior.

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Figure 1: Choice learning, shifting and relearning in a choice task.
Figure 2: Dynamic corticostriatal activation with choice learning and relearning.
Figure 3: In vivo striatal single-unit activity shifts with choice learning.
Figure 4: Striatal synaptic plasticity changes with choice learning.
Figure 5: Corticostriatal or striatal Grin2b deletion impairs choice learning.
Figure 6: Striatal GluN2B blockade impairs choice learning.
Figure 7: Cortical Grin2b deletion impairs choice shifting.
Figure 8: Orbitofrontal GluN2B blockade impairs choice shifting.

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References

  1. Middleton, F.A. & Strick, P.L. Basal-ganglia 'projections' to the prefrontal cortex of the primate. Cereb. Cortex 12, 926–935 (2002).

    Article  PubMed  Google Scholar 

  2. Mainen, Z.F. & Kepecs, A. Neural representation of behavioral outcomes in the orbitofrontal cortex. Curr. Opin. Neurobiol. 19, 84–91 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Schoenbaum, G., Roesch, M.R., Stalnaker, T.A. & Takahashi, Y.K. A new perspective on the role of the orbitofrontal cortex in adaptive behaviour. Nat. Rev. Neurosci. 10, 885–892 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Balleine, B.W. & O'Doherty, J.P. Human and rodent homologies in action control: corticostriatal determinants of goal-directed and habitual action. Neuropsychopharmacology 35, 48–69 (2010).

    Article  PubMed  Google Scholar 

  5. Montague, P.R., King-Casas, B. & Cohen, J.D. Imaging valuation models in human choice. Annu. Rev. Neurosci. 29, 417–448 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Graybiel, A.M. Habits, rituals, and the evaluative brain. Annu. Rev. Neurosci. 31, 359–387 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Yin, H.H. & Knowlton, B.J. The role of the basal ganglia in habit formation. Nat. Rev. Neurosci. 7, 464–476 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Montague, P.R., Dayan, P. & Sejnowski, T.J. A framework for mesencephalic dopamine systems based on predictive Hebbian learning. J. Neurosci. 16, 1936–1947 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Floresco, S.B. & Jentsch, J.D. Pharmacological enhancement of memory and executive functioning in laboratory animals. Neuropsychopharmacology 36, 227–250 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Carli, M., Baviera, M., Invernizzi, R.W. & Balducci, C. Dissociable contribution of 5–HT1A and 5–HT2A receptors in the medial prefrontal cortex to different aspects of executive control such as impulsivity and compulsive perseveration in rats. Neuropsychopharmacology 31, 757–767 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Dang, M.T. et al. Disrupted motor learning and long-term synaptic plasticity in mice lacking NMDAR1 in the striatum. Proc. Natl. Acad. Sci. USA 103, 15254–15259 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yin, H.H., Knowlton, B.J. & Balleine, B.W. Blockade of NMDA receptors in the dorsomedial striatum prevents action-outcome learning in instrumental conditioning. Eur. J. Neurosci. 22, 505–512 (2005).

    Article  PubMed  Google Scholar 

  13. Jin, X. & Costa, R.M. Start/stop signals emerge in nigrostriatal circuits during sequence learning. Nature 466, 457–462 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Monyer, H., Burnashev, N., Laurie, D.J., Sakmann, B. & Seeburg, P.H. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12, 529–540 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. Brigman, J.L. et al. Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning. J. Neurosci. 30, 4590–4600 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Duffy, S., Labrie, V. & Roder, J.C. d-Serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning. Neuropsychopharmacology 33, 1004–1018 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Dix, S., Gilmour, G., Potts, S., Smith, J.W. & Tricklebank, M. A within-subject cognitive battery in the rat: differential effects of NMDA receptor antagonists. Psychopharmacology (Berl.) 212, 227–242 (2010).

    Article  CAS  Google Scholar 

  18. Higgins, G.A., Ballard, T.M., Enderlin, M., Haman, M. & Kemp, J.A. Evidence for improved performance in cognitive tasks following selective NR2B NMDA receptor antagonist pre-treatment in the rat. Psychopharmacology (Berl.) 179, 85–98 (2005).

    Article  CAS  Google Scholar 

  19. von Engelhardt, J. et al. Contribution of hippocampal and extra-hippocampal NR2B-containing NMDA receptors to performance on spatial learning tasks. Neuron 60, 846–860 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Tang, Y.P. et al. Genetic enhancement of learning and memory in mice. Nature 401, 63–69 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Bussey, T.J. et al. New translational assays for preclinical modelling of cognition in schizophrenia: the touchscreen testing method for mice and rats. Neuropharmacology 62, 1191–1203 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Karlsson, R.M. et al. Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia. Neuropsychopharmacology 34, 1578–1589 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Brigman, J.L. et al. Pharmacological or genetic inactivation of the serotonin transporter improves reversal learning in mice. Cereb. Cortex 20, 1955–1963 (2010).

    Article  PubMed  Google Scholar 

  24. Graybeal, C. et al. Paradoxical reversal learning enhancement by stress or prefrontal cortical damage: rescue with BDNF. Nat. Neurosci. 14, 1507–1509 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Barnes, T.D., Kubota, Y., Hu, D., Jin, D.Z. & Graybiel, A.M. Activity of striatal neurons reflects dynamic encoding and recoding of procedural memories. Nature 437, 1158–1161 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Floresco, S.B., Zhang, Y. & Enomoto, T. Neural circuits subserving behavioral flexibility and their relevance to schizophrenia. Behav. Brain Res. 204, 396–409 (2009).

    Article  PubMed  Google Scholar 

  27. Alexander, W.H. & Brown, J.W. Medial prefrontal cortex as an action-outcome predictor. Nat. Neurosci. 14, 1338–1344 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ragozzino, M.E. The contribution of the medial prefrontal cortex, orbitofrontal cortex, and dorsomedial striatum to behavioral flexibility. Ann. NY Acad. Sci. 1121, 355–375 (2007).

    Article  PubMed  Google Scholar 

  29. Corbit, L.H. & Janak, P.H. Posterior dorsomedial striatum is critical for both selective instrumental and Pavlovian reward learning. Eur. J. Neurosci. 31, 1312–1321 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Costa, R.M., Cohen, D. & Nicolelis, M.A. Differential corticostriatal plasticity during fast and slow motor skill learning in mice. Curr. Biol. 14, 1124–1134 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Dickinson, A. Actions and habits: the development of behavioural autonomy. Philos. Trans. R. Soc. Lond. B Biol. 308, 67–78 (1985).

    Article  Google Scholar 

  32. Gage, G.J., Stoetzner, C.R., Wiltschko, A.B. & Berke, J.D. Selective activation of striatal fast-spiking interneurons during choice execution. Neuron 67, 466–479 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kravitz, A.V. et al. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 466, 622–626 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tang, C., Pawlak, A.P., Prokopenko, V. & West, M.O. Changes in activity of the striatum during formation of a motor habit. Eur. J. Neurosci. 25, 1212–1227 (2007).

    Article  PubMed  Google Scholar 

  35. Pasupathy, A. & Miller, E.K. Different time courses of learning-related activity in the prefrontal cortex and striatum. Nature 433, 873–876 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Yin, H.H. et al. Dynamic reorganization of striatal circuits during the acquisition and consolidation of a skill. Nat. Neurosci. 12, 333–341 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Schultz, W. et al. Explicit neural signals reflecting reward uncertainty. Phil. Trans. R. Soc. Lond. B 363, 3801–3811 (2008).

    Article  Google Scholar 

  38. Calabresi, P., Maj, R., Pisani, A., Mercuri, N.B. & Bernardi, G. Long-term synaptic depression in the striatum: physiological and pharmacological characterization. J. Neurosci. 12, 4224–4233 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ashby, F.G., Turner, B.O. & Horvitz, J.C. Cortical and basal ganglia contributions to habit learning and automaticity. Trends Cogn. Sci. 14, 208–215 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Wickens, J.R., Horvitz, J.C., Costa, R.M. & Killcross, S. Dopaminergic mechanisms in actions and habits. J. Neurosci. 27, 8181–8183 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ryan, T.J. et al. Evolution of GluN2A/B cytoplasmic domains diversified vertebrate synaptic plasticity and behavior. Nat. Neurosci. 16, 25–32 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Brigman, J.L. et al. Impaired discrimination learning in mice lacking the NMDA receptor NR2A subunit. Learn. Mem. 15, 50–54 (2008).

    Article  PubMed  Google Scholar 

  43. Fukaya, M., Kato, A., Lovett, C., Tonegawa, S. & Watanabe, M. Retention of NMDA receptor NR2 subunits in the lumen of endoplasmic reticulum in targeted NR1 knockout mice. Proc. Natl. Acad. Sci. USA 100, 4855–4860 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dalton, G.L., Wang, Y.T., Floresco, S.B. & Phillips, A.G. Disruption of AMPA receptor endocytosis impairs the extinction, but not acquisition of learned fear. Neuropsychopharmacology 33, 2416–2426 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Higgins, G.A., Ballard, T.M., Huwyler, J., Kemp, J.A. & Gill, R. Evaluation of the NR2B-selective NMDA receptor antagonist Ro 63–1908 on rodent behaviour: evidence for an involvement of NR2B NMDA receptors in response inhibition. Neuropharmacology 44, 324–341 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Kos, T., Nikiforuk, A., Rafa, D. & Popik, P. The effects of NMDA receptor antagonists on attentional set-shifting task performance in mice. Psychopharmacology (Berl.) 214, 911–921 (2011).

    Article  CAS  Google Scholar 

  47. Vanderschuren, L.J., Di Ciano, P. & Everitt, B.J. Involvement of the dorsal striatum in cue-controlled cocaine seeking. J. Neurosci. 25, 8665–8670 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bohn, I., Giertler, C. & Hauber, W. NMDA receptors in the rat orbital prefrontal cortex are involved in guidance of instrumental behaviour under reversal conditions. Cereb. Cortex 13, 968–976 (2003).

    Article  PubMed  Google Scholar 

  49. Parker, J.G., Beutler, L.R. & Palmiter, R.D. The contribution of NMDA receptor signaling in the corticobasal ganglia reward network to appetitive Pavlovian learning. J. Neurosci. 31, 11362–11369 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wang, L.P. et al. NMDA receptors in dopaminergic neurons are crucial for habit learning. Neuron 72, 1055–1066 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Izquierdo, A. et al. Genetic and dopaminergic modulation of reversal learning in a touchscreen-based operant procedure for mice. Behav. Brain Res. 171, 181–188 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Hefner, K. et al. Impaired fear extinction learning and cortico-amygdala circuit abnormalities in a common genetic mouse strain. J. Neurosci. 28, 8074–8085 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Karlsson, R.M., Tanaka, K., Heilig, M. & Holmes, A. Loss of glial glutamate and aspartate transporter (excitatory amino acid transporter 1) causes locomotor hyperactivity and exaggerated responses to psychotomimetics: rescue by haloperidol and metabotropic glutamate 2/3 agonist. Biol. Psychiatry 64, 810–814 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Dahlin, E., Neely, A.S., Larsson, A., Backman, L. & Nyberg, L. Transfer of learning after updating training mediated by the striatum. Science 320, 1510–1512 10.1126/science.1155466 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Erickson, K.I. et al. Training-induced functional activation changes in dual-task processing: An fMRI study. Cereb. Cortex 17, 192–204 (2007).

    Article  PubMed  Google Scholar 

  56. Olesen, P.J., Westerberg, H. & Klingberg, T. Increased prefrontal and parietal activity after training of working memory. Nat. Neurosci. 7, 75–79 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Boyce-Rustay, J.M. & Holmes, A. Ethanol-related behaviors in mice lacking the NMDA receptor NR2A subunit. Psychopharmacology (Berl.) 187, 455–466 (2006).

    Article  CAS  Google Scholar 

  58. Holmes, A. et al. Chronic alcohol remodels prefrontal neurons and disrupts NMDAR-mediated fear extinction encoding. Nat. Neurosci. 15, 1359–1361 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are very grateful to G. Schoenbaum and A. Kravitz for discussions of the in vivo recording results and to G. Luo for mutant genotyping. J.L.B., C.G., T.W., M.I.D., R.A.D., M.P., O.G.-C., D.M.L. and A.H. were supported by the NIAAA Intramural Research Program. L.M.S. and T.J.B. were supported by The Wellcome Trust. Z.J. and K.N. were supported by the National Institute of Mental Health Intramural Research Program.

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Authors and Affiliations

  1. Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse (NIAAA), US National Institutes of Health (NIH), Bethesda, Maryland, USA

    Jonathan L Brigman, Rachel A Daut, Tara Wright, Ozge Gunduz-Cinar, Carolyn Graybeal, Matthew Pease & Andrew Holmes

  2. Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, Bethesda, Maryland, USA

    Margaret I Davis & David M Lovinger

  3. Unit on Genetics of Cognition and Behavior, National Institute of Mental Health, NIH, Bethesda, Maryland, USA

    Zhihong Jiang, Seiichiro Jinde & Kazu Nakazawa

  4. Department of Experimental Psychology, University of Cambridge, Cambridge, UK

    Lisa M Saksida & Timothy J Bussey

  5. Medical Research Council and Wellcome Trust Behavioral and Clinical Neuroscience Institute, Cambridge, UK

    Lisa M Saksida & Timothy J Bussey

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  1. Jonathan L Brigman
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Contributions

J.L.B. conducted behavioral, c-Fos, in vivo electrophysiological and in situ hybridization experiments and contributed to writing the manuscript; R.A.D., C.G. and M.P. conducted behavioral experiments; T.W. conducted the slice electrophysiological experiments; O.G.-C. conducted RT-PCR and western blot experiments; M.I.D. contributed to the c-Fos experiments; Z.J. and S.J. contributed to the in situ hybridization experiments; L.M.S. and T.J.B. provided behavioral analysis software; D.M.L. supervised the slice electrophysiological experiments and contributed to writing the manuscript; K.N. supervised the in situ hybridization experiments, provided mutant mice and contributed to writing the manuscript; A.H. supervised the study and contributed to writing the manuscript.

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Correspondence to Andrew Holmes.

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Brigman, J., Daut, R., Wright, T. et al. GluN2B in corticostriatal circuits governs choice learning and choice shifting. Nat Neurosci 16, 1101–1110 (2013). https://doi.org/10.1038/nn.3457

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